ironjustice
2013-05-26 16:42:34 UTC
Intensified, Liposomal Anthracycline-Based Chemo Regimen For Children
With Leukemia May Offer High Survival Rates Without Added Heart
Toxicity
25 May 2013 - 0:00 PDT
Treating pediatric leukemia patients with a liposomal formulation of
anthracycline-based chemotherapy at a more intense-than-standard dose
during initial treatment may result in high survival rates without
causing any added heart toxicity, according to the results of a study
published online today in Blood, the Journal of the American Society
of Hematology (ASH).
Acute myeloid leukemia (AML), the second most common form of leukemia
in children, is a blood cancer in which the bone marrow makes a large
number of abnormal white blood cells that crowd out other healthy
blood cells over time, leading to infection, anemia, or excessive
bleeding. Most adults and children with AML receive a first line of
treatment (known as induction therapy) soon after diagnosis with a
class of chemotherapy drugs called anthracyclines. Standard induction
regimens in children typically consist of three days of an
anthracycline such as daunorubicin or idarubicin and seven to 10 days
of another chemotherapy such as cytarabine. Approximately 60 to 70
percent of children with AML achieve long-term survival with this
combination of drugs.
Recent evidence has suggested that increasing the intensity of
induction treatment might improve remission rates and perhaps overall
survival in AML patients. However, clinicians have used this approach
sparingly in pediatric patients because of documented dose-related
anthracycline toxicity in children, particularly the significant risk
of damage to the developing heart muscle. In an effort to increase the
effectiveness of this treatment for children with AML but reduce the
cardiac risk profile, researchers are now investigating a liposomal
(or lipid-based) formulation of the anthracycline daunorubicin (L-DNR)
that allows for more targeted delivery of the drug in the cancerous
cells and diffuses at a slower pace in the body which leads to a lower
accumulation in the heart. Results from early pre-clinical studies of
the lipid-based formulation suggest that L-DNR may be effective at
higher-than-standard doses without causing added cardiotoxicity.
"We know that the standard induction treatment regimen is effective in
pediatric leukemia patients, but recognize that the toxicities
associated with this therapy can be damaging to young patients who are
still growing and developing," said lead study author Ursula Creutzig,
MD, of the Hannover Medical School in Germany. "This unique
formulation of daunorubicin might offer us a way to effectively manage
AML in these young patients while reducing their risk of experiencing
the acute and long-term toxicities associated with traditional
regimens."
To evaluate this hypothesis, Dr. Creutzig and a team of researchers
initiated a trial to determine if L-DNR at intensified dosages in
child and adolescent patients would improve their outcomes without
added treatment-related acute and long-term cardiotoxicity. Between
2004 and 2010, 521 patients under 18 years of age were randomly
assigned to treatment with either L-DNR or idarubicin induction
therapy. Patients treated with L-DNR received a higher dose (80 mg/m²/
day/x3) than the equivalent dose of idarubicin (12 mg/m²/day/x3)
during induction. Both groups also received additional treatment with
cytarabine and etoposide. High-risk patients (defined roughly as those
who were not in the favorable cytogenetic group) also received
supplemental treatment with a chemotherapeutic agent (2-CDA) after the
induction period. Additional cycles of maintenance treatment were
administered to all participants, excluding those who received a stem
cell transplant.
After a five-year observational period, researchers noted similar
results in both treatment arms (76% overall survival in the L-DNR
group vs. 75% in the idarubicin group). The probability of event-free
survival (or pEFS) was also similar in the L-DNR (59%) and idarubicin
groups (53%), as were pEFS results for standard risk (72% for L-DNR
vs. 68% for idarubin) and high-risk patients (51% vs. 46%,
respectively).
Overall, treatment with this intensified induction regimen had a
similar safety and tolerability profile to the traditional idarubicin
dose. Treatment-related mortality was lower in the L-DNR group than in
the idarubicin group (2/257 vs. 10/264 patients), and there were no
unusual or persistent toxicities seen when compared with previous
related trials. The team observed generally low rates of
cardiotoxicities across the treatment groups in the study, though
fewer events were reported among the L-DNR treated patients than the
idarubicin-treated patients. In the L-DNR group, there were four
reports of severe acute cardiotoxicities, such as functional
impairment, versus five events in the idarubicin group. There was a
single patient reported to have late cardiotoxicity during follow-up
in the L-DNR group, as compared with three patients in the idarubicin
treatment group.
"These findings signal an important step forward in our goal to
identify treatments that can give pediatric patients the best chance
for long-term survival with minimal toxic side effects, and we believe
the approach could have a number of extended applications. For
example, this treatment formulation may be appropriate to use in
adults or elderly patients to reduce the toxicity profile, or it may
be of value for other malignant diseases in both children and adults,"
said Dr. Creutzig. "We look forward to further investigating L-DNR as
the standard anthracycline induction treatment in future studies."
----------------
Iron Chelation by Clinically Relevant Anthracyclines: Alteration in
Expression of Iron-Regulated Genes and Atypical Changes in
Intracellular Iron Distribution and Trafficking.
Xu X, Sutak R, Richardson DR.
Mol Pharmacol. 2007 Nov 20
University of Sydney.
Anthracyclines are effective anti-cancer agents.
However, their use is limited by cardiotoxicity, an effect linked
to their ability to chelate iron (Fe) and perturb Fe metabolism
(Xu X, Persson L and Richardson DR Mol Pharmacol 68:261-271, 2005).
These effects on Fe-trafficking remain poorly understood, but are
important to decipher as treatment for anthracycline cardiotoxicity
utilizes the chelator, dexrazoxane.
Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels
of the Fe-regulated genes, transferrin receptor-1 (TfR1) and N-myc
downstream-regulated gene-1 (Ndrg1).
This effect was mediated by Fe-depletion, as it was reversed by
adding Fe and was prevented by saturating the anthracycline
metal-binding site with Fe.
However, DOX did not act like a typical chelator, as it did not
induce
cellular Fe mobilization.
In the presence of DOX and (59)Fe-transferrin, Fe-trafficking studies
demonstrated ferritin-(59)Fe accumulation and decreased cytosolic-
(59)Fe incorporation.
This could induce cytosolic Fe-deficiency and increase TfR1 and Ndrg1
mRNA.
Up-regulation of TfR1 and Ndrg1 by DOX was independent of
anthracycline- mediated radical generation and occurred via HIF-1alpha-
independent
mechanisms.
Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent
decreased TfR1 and Ndrg1 protein due to inhibition of translation.
Hence, the effects of DOX on Fe metabolism were complex due to its
multiple effector mechanisms.
PMID: 18029550
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
With Leukemia May Offer High Survival Rates Without Added Heart
Toxicity
25 May 2013 - 0:00 PDT
Treating pediatric leukemia patients with a liposomal formulation of
anthracycline-based chemotherapy at a more intense-than-standard dose
during initial treatment may result in high survival rates without
causing any added heart toxicity, according to the results of a study
published online today in Blood, the Journal of the American Society
of Hematology (ASH).
Acute myeloid leukemia (AML), the second most common form of leukemia
in children, is a blood cancer in which the bone marrow makes a large
number of abnormal white blood cells that crowd out other healthy
blood cells over time, leading to infection, anemia, or excessive
bleeding. Most adults and children with AML receive a first line of
treatment (known as induction therapy) soon after diagnosis with a
class of chemotherapy drugs called anthracyclines. Standard induction
regimens in children typically consist of three days of an
anthracycline such as daunorubicin or idarubicin and seven to 10 days
of another chemotherapy such as cytarabine. Approximately 60 to 70
percent of children with AML achieve long-term survival with this
combination of drugs.
Recent evidence has suggested that increasing the intensity of
induction treatment might improve remission rates and perhaps overall
survival in AML patients. However, clinicians have used this approach
sparingly in pediatric patients because of documented dose-related
anthracycline toxicity in children, particularly the significant risk
of damage to the developing heart muscle. In an effort to increase the
effectiveness of this treatment for children with AML but reduce the
cardiac risk profile, researchers are now investigating a liposomal
(or lipid-based) formulation of the anthracycline daunorubicin (L-DNR)
that allows for more targeted delivery of the drug in the cancerous
cells and diffuses at a slower pace in the body which leads to a lower
accumulation in the heart. Results from early pre-clinical studies of
the lipid-based formulation suggest that L-DNR may be effective at
higher-than-standard doses without causing added cardiotoxicity.
"We know that the standard induction treatment regimen is effective in
pediatric leukemia patients, but recognize that the toxicities
associated with this therapy can be damaging to young patients who are
still growing and developing," said lead study author Ursula Creutzig,
MD, of the Hannover Medical School in Germany. "This unique
formulation of daunorubicin might offer us a way to effectively manage
AML in these young patients while reducing their risk of experiencing
the acute and long-term toxicities associated with traditional
regimens."
To evaluate this hypothesis, Dr. Creutzig and a team of researchers
initiated a trial to determine if L-DNR at intensified dosages in
child and adolescent patients would improve their outcomes without
added treatment-related acute and long-term cardiotoxicity. Between
2004 and 2010, 521 patients under 18 years of age were randomly
assigned to treatment with either L-DNR or idarubicin induction
therapy. Patients treated with L-DNR received a higher dose (80 mg/m²/
day/x3) than the equivalent dose of idarubicin (12 mg/m²/day/x3)
during induction. Both groups also received additional treatment with
cytarabine and etoposide. High-risk patients (defined roughly as those
who were not in the favorable cytogenetic group) also received
supplemental treatment with a chemotherapeutic agent (2-CDA) after the
induction period. Additional cycles of maintenance treatment were
administered to all participants, excluding those who received a stem
cell transplant.
After a five-year observational period, researchers noted similar
results in both treatment arms (76% overall survival in the L-DNR
group vs. 75% in the idarubicin group). The probability of event-free
survival (or pEFS) was also similar in the L-DNR (59%) and idarubicin
groups (53%), as were pEFS results for standard risk (72% for L-DNR
vs. 68% for idarubin) and high-risk patients (51% vs. 46%,
respectively).
Overall, treatment with this intensified induction regimen had a
similar safety and tolerability profile to the traditional idarubicin
dose. Treatment-related mortality was lower in the L-DNR group than in
the idarubicin group (2/257 vs. 10/264 patients), and there were no
unusual or persistent toxicities seen when compared with previous
related trials. The team observed generally low rates of
cardiotoxicities across the treatment groups in the study, though
fewer events were reported among the L-DNR treated patients than the
idarubicin-treated patients. In the L-DNR group, there were four
reports of severe acute cardiotoxicities, such as functional
impairment, versus five events in the idarubicin group. There was a
single patient reported to have late cardiotoxicity during follow-up
in the L-DNR group, as compared with three patients in the idarubicin
treatment group.
"These findings signal an important step forward in our goal to
identify treatments that can give pediatric patients the best chance
for long-term survival with minimal toxic side effects, and we believe
the approach could have a number of extended applications. For
example, this treatment formulation may be appropriate to use in
adults or elderly patients to reduce the toxicity profile, or it may
be of value for other malignant diseases in both children and adults,"
said Dr. Creutzig. "We look forward to further investigating L-DNR as
the standard anthracycline induction treatment in future studies."
----------------
Iron Chelation by Clinically Relevant Anthracyclines: Alteration in
Expression of Iron-Regulated Genes and Atypical Changes in
Intracellular Iron Distribution and Trafficking.
Xu X, Sutak R, Richardson DR.
Mol Pharmacol. 2007 Nov 20
University of Sydney.
Anthracyclines are effective anti-cancer agents.
However, their use is limited by cardiotoxicity, an effect linked
to their ability to chelate iron (Fe) and perturb Fe metabolism
(Xu X, Persson L and Richardson DR Mol Pharmacol 68:261-271, 2005).
These effects on Fe-trafficking remain poorly understood, but are
important to decipher as treatment for anthracycline cardiotoxicity
utilizes the chelator, dexrazoxane.
Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels
of the Fe-regulated genes, transferrin receptor-1 (TfR1) and N-myc
downstream-regulated gene-1 (Ndrg1).
This effect was mediated by Fe-depletion, as it was reversed by
adding Fe and was prevented by saturating the anthracycline
metal-binding site with Fe.
However, DOX did not act like a typical chelator, as it did not
induce
cellular Fe mobilization.
In the presence of DOX and (59)Fe-transferrin, Fe-trafficking studies
demonstrated ferritin-(59)Fe accumulation and decreased cytosolic-
(59)Fe incorporation.
This could induce cytosolic Fe-deficiency and increase TfR1 and Ndrg1
mRNA.
Up-regulation of TfR1 and Ndrg1 by DOX was independent of
anthracycline- mediated radical generation and occurred via HIF-1alpha-
independent
mechanisms.
Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent
decreased TfR1 and Ndrg1 protein due to inhibition of translation.
Hence, the effects of DOX on Fe metabolism were complex due to its
multiple effector mechanisms.
PMID: 18029550
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk